Skeletal muscle atrophy is characteristic of starvation and a common effect of aging. It is also a nearly universal consequence of severe human illnesses, including cancer, chronic renal failure, congestive heart failure, chronic respiratory disease, insulin deficiency, acute critical illness, chronic infections such as HIV/AIDS, muscle denervation, and many other medical and surgical conditions. Prior to 2010, medical therapies to prevent or reverse skeletal muscle atrophy in human patients did not exist. As a result, millions of individuals suffered sequelae of muscle atrophy, including weakness, falls, fatigue, impaired recovery from illness and injury, fractures, and loss of independence. The burden that skeletal muscle atrophy places on individuals, their families, and society in general, is tremendous.
The pathogenesis of skeletal muscle atrophy was not formerly well understood, but important advances have been made. For example, it has been described previously that insulin/IGF1 signaling promotes muscle hypertrophy and inhibits muscle atrophy, but is reduced by atrophy-inducing stresses such as fasting or muscle denervation (Bodine S C, et al. (2001) Nat Cell Biol 3(11):1014-1019; Sandri M, et al. (2004) Cell 117(3):399-4121; Stitt T N, et al. (2004) Mol Cell 14(3):395-403; Hu Z, et al. (2009) The Journal of clinical investigation 119(10):3059-3069; Dobrowolny G, et al. (2005) The Journal of cell biology 168(2):193-199; Kandarian S C & Jackman R W (2006) Muscle & nerve 33(2):155-165; Hirose M, et al. (2001) Metabolism: clinical and experimental 50(2):216-222; Pallafacchina G, et al. (2002) Proceedings of the National Academy of Sciences of the United States of America 99(14):9213-9218). The hypertrophic and anti-atrophic effects of insulin/IGF1 signaling are mediated at least in part through increased activity of phosphoinositide 3-kinase (PI3K) and its downstream effectors, including Akt and mammalian target of rapamycin complex 1 (mTORC1) Sandri M (2008) Physiology (Bethesda) 23:160-170; Glass D J (2005) The international journal of biochemistry & cell biology 37(10): 1974-1984).
Another important advance came from microarray studies of atrophying rodent muscle (Lecker S H, et al. (2004) Faseb J 18(1):39-51; Sacheck J M, et al. (2007) Faseb J 21(1): 140-155; Jagoe R T, et al. Faseb J 16(13): 1697-1712). Those studies showed that several seemingly disparate atrophy-inducing stresses (including fasting, muscle denervation and severe systemic illness) generated many common changes in skeletal muscle mRNA expression. Some of those atrophy-associated changes promote muscle atrophy in mice; these include induction of the mRNAs encoding atroginI/MAFbx and MuRF1 (two E3 ubiquitin ligases that catalyze proteolytic events), and repression of the mRNA encoding PGC-1α (a transcriptional co-activator that inhibits muscle atrophy) (Sandri M, et al. (2006) Proceedings of the National Academy of Sciences of the United States of America 103(44): 16260-16265; Wenz T, et al. Proceedings of the National Academy of Sciences of the United States of America 106(48):20405-20410; Bodine S C, et al. (2001) Science (New York, N.Y. 294(5547): 1704-1708; Lagirand-Cantaloube J, et al. (2008) The EMBO journal 27(8): 1266-1276; Cohen S, et al. (2009) The Journal of cell biology 185(6):1083-1095; Adams V, et al. (2008) Journal of molecular biology 384(1):48-59). However, the roles of many other mRNAs that are increased or decreased in atrophying rodent muscle are not yet defined. Data on the mechanisms of human muscle atrophy are even more limited, although atrogin-1 and MuRF1 are likely to be involved (Leger B, et al. (2006) Faseb J 20(3):583-585; Doucet M, et al. (2007) American journal of respiratory and critical care medicine 176(3):261-269; Levine S, et al. (2008) The New England journal of medicine 358(13): 1327-1335).
In 2010 results began appearing from the laboratory of Christopher Adams at the University of Iowa; these are reflected in published US applications 2013/0203712, 2014/0228333, 2014/0371188 and 2015/0164918. These breakthrough studies provided evidence that small molecule therapeutics were capable of increasing skeletal muscle mass and strength in vivo.
The furostanol scaffold of the compounds described below is found primarily in the aglycone portion of plant saponins. The plant saponins are frequently associated in the literature with various biological activities, but therapeutic properties are not commonly ascribed to the unglycosylated furostanol sapogenins. For example, US published application 2007/0254847 describes a class of saponins obtained from Dioscorea panthaica and Dioscorea nipponica which are said to possess utility in treating cerebrovascular and coronary heart diseases. Although the glycosides share a furostanol core, it is the glycoside saponin, not the furostanol aglycone to which the utility is ascribed.